Cilastatin is a renal dehydropeptidase inhibitor and its sodium salt is co-administered with imipenem for purpose of preventing renal metabolism of imipenem. The composition containing imipenem and cilastatin is used as a potent broad-spectrum antibacterial agent.
Cilastatin was first disclosed in U.S. Pat. No. 5,147,868, which was synthesized by multi-steps reactions including synthesis of ethyl 7-chloro-2-oxoheptylate by Gringnard reaction of 1-bromo-5-chloropentane with excessive diethyl oxalate. The method was improved by CHEN Xin-zhi et al in the Chinese patent application No. CN1587248A, but the total yield was only 24-43%, and the content of the resulting ethyl 7-chloro-2-oxoheptylate was merely 30-40%. Experiments showed that the content of the resulting product was only 30%, and it was difficult to be isolated and purified to obtain ethyl 7-chloro-2-oxoheptylate with high purity.
Methods for preparing ethyl 7-bromo-2-oxoheptylate by use of 1,5-dibromopentane, ethyl diethoxyacetate, propanedithiol, and so on as starting materials through reactions such as, cyclization, substitution, oxidization, etc. are disclosed in J. Med. Chem., 1987, 30 (6): 1074-1090 and Journal of Chinese Pharmaceuticals, 2005, 36(9), 531. However, these methods are not suitable for industrial production due to the expensive starting materials in these methods and the putrid propanedithiol.
PCT application WO98/15520 discloses a preparation method for obtaining ethyl 7-chloro-2-oxoheptylate with higher purity, in which 1-bromo-5-chloropentane and ethyl acetoacetate are used as starting materials, which are subjected to substitution reaction, then nitrosificated with nitroso-sulfuric acid, and deacetylated under acidic condition, and then reacted with formaldehyde to convert an oxime to a ketone, and finally refined by sodium bisulfite. However, expensive starting materials are still used in this method and large amount of waste acids are produced during nitrosification, which is not environment friendly.
Thus, a novel method of preparing an intermediate of cilastatin is still required in the field.